a) For over twenty years, our team has contributed to identify and study the molecular building blocks that coordinate the development of the vertebrate visual system. Building on this experience, we are now investigating how the retinal pigmented epithelium (RPE) forms and contributes to the overall architecture of the eye. The RPE consists of a monolayer of cells, positioned at the back of the neural retina. This tissue has the critical function of protecting, nourishing and cooperating with the light sensing cells of the retina: the photoreceptors. The cells of the RPE are initially neuroepithelial as those of the neural retina but soon transform in a cuboidal/squamous pigmented layer (Figure 1). The events underlying this transformation are still poorly understood. Using the zebrafish and chick embryos as models, we are studying the cellular and molecular aspects of this transformation and are further asking whether this transformation is necessary for the acquisition of the final cup-shape that the vertebrate eye has. In other words, we want to know what happens to the eye if the RPE does not develop correctly. As an extension of this question, we are also asking how the entire visual system adapts to the abnormal development of one of its parts. For example, what happens to the eye if the thalamic visual structures do not form in an appropriate manner?

b) When the brain ages, the number of functional connections among neurons decreases and the brain assume a state of low but chronic “inflammation”. These changes are exacerbated in neurodegenerative diseases such as Alzheimer’s Disease (AD), in which there is also an accumulation of typical “amyloid plaques” (Figure 2). From a molecular point of view, loss of connections, inflammation and amyloid plaque formation have a commonality: the activity of the metalloprotease ADAM10. We have recently shown that a small secreted protein, known as Secreted Frizzled Related Protein 1 (SFRP1), acts as an endogenous inhibitor of ADAM10. Based on this observation, we hypothesized that abnormally upregulated SFRP1 levels in the brain of AD patients could impair ADAM10 activity and be a common trait of AD. Our work has validated this hypothesis, demonstrating that SFRP1 contributes to AD pathogenesis, whereas neutralization of its activity in a mouse model prevents the progression of the disease and the loss of memory present in AD (or in aging). Based on this exciting result and taking advantage of different transgenic mouse models that we have generated, we are now investigating the direct implication of Sfrp1 in the loss of brain connections and in the inflammatory events that take place in AD and aging. We are further exploring the potential of SFRP1 neutralization as a therapeutic strategy against AD.